title: Francisella tularensis SchuS4 and SchuS4 lipids inhibit IL-12p40 in primary human dendritic cells by inhibition of IRF1 and IRF8.
abstract: Induction of innate immunity is essential for host survival of infection. Evasion and inhibition of innate immunity constitute a strategy used by pathogens, such as the highly virulent bacterium Francisella tularensis, to ensure their replication and transmission. The mechanism and bacterial components responsible for this suppression of innate immunity by F. tularensis are not defined. In this article, we demonstrate that lipids enriched from virulent F. tularensis strain SchuS4, but not attenuated live vaccine strain, inhibit inflammatory responses in vitro and in vivo. Suppression of inflammatory responses is associated with IκBα-independent inhibition of NF-κBp65 activation and selective inhibition of activation of IFN regulatory factors. Interference with NF-κBp65 and IFN regulatory factors is also observed following infection with viable SchuS4. Together these data provide novel insight into how highly virulent bacteria selectively modulate the host to interfere with innate immune responses required for survival of infection.
authors.affiliation: Immunity to Pulmonary Pathogens Section, Laboratory of Intracellular Parasites, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Ireland
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Alinger
authors.forename: Pamela
authors.initials: P
authors.lastname: Small
authors.forename: Catharine M
authors.initials: CM
authors.lastname: Bosio
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005604:Francisella tularensis / Q000276:immunology / Q000472:pathogenicity; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors; D057131:Immune Evasion; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D050856:Interferon Regulatory Factor-1 / Q000037:antagonists & inhibitors*; D050835:Interferon Regulatory Factors / Q000037:antagonists & inhibitors*; D053762:Interleukin-12 Subunit p40 / Q000037:antagonists & inhibitors* / Q000276:immunology; D008055:Lipids / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors*; D014406:Tularemia / Q000276:immunology / Q000382:microbiology; D000099185:Interferon Regulatory Factor-8
chemical_list: D000907:Antibodies, Bacterial; D020672:I-kappa B Proteins; D050856:Interferon Regulatory Factor-1; D050835:Interferon Regulatory Factors; D053762:Interleukin-12 Subunit p40; D008055:Lipids; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D051996:Transcription Factor RelA; D000099185:Interferon Regulatory Factor-8; C494258:Irf1 protein, mouse; C000606204:NFKBIA protein, human; C000606205:Nfkbia protein, mouse; C498144:Rela protein, mouse